Plasmacytoid dendritic cell precursors (pDCs) play a key role at the interface of innate and acquired immunity in anti-viral responses by sensing viral infection through TLR7/TLR9 and rapidly producing large amounts of type 1 interferons (IFNs). However, several recent studies have also identified pDC as critical players in oral and airway tolerance. This is consistent with the findings that pDCs are capable of inducing development of regulatory T cells (Treg), known to be immunosuppressive. pDCs infiltrate many human tumors. In breast tumors, pDC infiltration is associated with poor survival. More recent studies showed that pDC infiltration plays a critical role in the induction of immune suppression in ovarian cancer and in promoting tumor cell growth, survival and drug resistance in human multiple myeloma (MM). However, the molecular mechanisms underlying the role of pDCs in the generation and maintenance of immune tolerance and in promoting myeloma cell growth, survival and drug resistance are unknown. We have recently identified a pDC-specific receptor complex ILT7/FceR?1 (pDCR) and its ligand BST2. Signaling through pDCR induces a BCR-like signal cascade that potently inhibits TLR7/9-mediated type 1 IFN responses by pDCs. Interestingly, BST2 is highly expressed by myeloma cells, suggesting that myeloma cells may directly inhibit the innate immune function of pDCs via BST2 and ILT7 interaction. Our hypothesis is that human myeloma cells may inhibit the innate immune function of pDCs via BST2/ILT7 interaction and enhance the tolerogenic function of pDCs within the myeloma tumor microenvironment. We recently generated monoclonal antibodies to BST2, which can be used to directly kill myeloma cells by antibody-mediated cytotoxicity, block the immunosuppressive function of pDCs and promote the innate immune function of pDCs when activated by a TLR9 ligand. We propose the following aims: Aim 1 will determine whether human myeloma-infiltrating pDCs display gene and signaling signatures induced by BST2/ILT7 interaction and have enhanced function for inducing immune tolerance; Aim 2 will establish the role of ILT7 and BST2 interaction in myeloma-induced dysfunction of pDCs in the myeloma microenvironment; and finally, Aim 3 will develop a new strategy to reprogram pDCs from inducing tolerance to inducing anti-viral-like anti-tumor immunity in MM. Such studies will result in the development of novel combinational therapies, such as chemotherapy drugs plus BST2/ILT7 blocking antibodies, for the treatment of myeloma patients; they will also improve our understanding of the mechanisms and significance of simultaneously immunotargeting MM cells and pDCs to restore the immune system and maximize the efficacy of cancer treatments.